Skeletal patterning begins during embryogenesis when mesenchymal stem cells (MSC) condensate into elements that prefigure the future bone. Formation of the embryologic skeleton proceeds through a complex process of both endochondral and intramembranous ossification. During intramembranous ossification and postnatal skeletal formation, the mesenchyamal stem cells give rise to osteoblasts, which synthesize the matrix constituents on bone forming surfaces. Following the initial commitment to the osteoblast lineage, the osteoprogenitor cells continues to proliferate and proceed through a series of developmental stages that culminate in the generation of the mature osteoblast that is responsible for synthesizing extracellular matrix. Proliferation, differentiation and bone remodeling activities of osteoblasts involve a complex temporal network of growth factors, signaling proteins, and transcription factors, of which many have yet to be identified. The broad objectives of this project are to expand our understanding of the transcriptional and signaling mechanisms that govern the differentiation and activation of osteoblasts during skeletal formation and remodeling. The candidate's proposal focuses on the regulation of WWP1 in osteoblast biology by building upon the candidates recent finding that identified the zinc-finger adapter protein Schnurri-3 (Shn3) as an essential regulator of osteoblast synthetic acitivity through its interaction with WWP1. The candidate has taken an unbiased approach to identify novel regulators of osteoblast differentiation from mesechymal stem cells. Conducting the mentored phase of the project in the laboratory of Dr. Laurie Glimcher will provide an ideal environment to develop the foundation necessary for continuing to research the molecular events that govern the process of bone remodeling during the independent phase in the candidates own academic lab. Relevance: Functional deregulation of osteoblasts affects bone mass and contributes to the pathogenesis of skeletal disorders, including osteoporosis, erosive arthritis and primary and metastatic bone malignancies. As the population in the United States ages, the incidence of these diseases will increase and present an expanding source of morbidity and mortality. A complete molecular understanding of osteoblast biology will provide for better therapeutic targets to help protect and possibly restore those tissue that have been compromised during the these various skeletal disorders.